Benzimidazole urea derivatives, and pharmaceutical compositions and unit dosages thereof

ABSTRACT

Benzimidazole derivatives and salts and prodrugs thereof are disclosed, together with methods for the treatment of cancers or viral infections in warm blooded animals by administration of these compounds. Such compounds may be used in combination with a chemotherapeutic agent and/or a potentiator.

TECHNICAL FIELD

The present invention relates to benzimidazole derivatives and their usefor the treatment of cancer or a viral infection in warm bloodedanimals, particularly in humans and other mammals. The methods may usesuch a compound in combination with a potentiator or a chemotherapeuticagent.

BACKGROUND OF THE INVENTION

Cancers are a leading cause of death in animals and humans. The exactcause of cancer is not known, but links between certain activities suchas smoking or exposure to carcinogens and the incidence of certain typesof cancers and tumors has been shown by a number of researchers.

Many types of chemotherapeutic agents have been shown to be effectiveagainst cancers and tumor cells, but not all types of cancers and tumorsrespond to these agents. Unfortunately, many of these agents alsodestroy normal cells. The exact mechanism for the action of thesechemotherapeutic agents are not always known.

Despite advances in the field of cancer treatment the leading therapiesto date are surgery, radiation and chemotherapy. Chemotherapeuticapproaches are said to fight cancers that are metastasized or ones thatare particularly aggressive. Such cytocidal or cytostatic agents workbest on cancers with large growth factors, i.e., ones whose cells arerapidly dividing. To date, hormones, in particular estrogen,progesterone and testosterone, and some antibiotics produced by avariety of microbes, alkylating agents, and anti-metabolites form thebulk of therapies available to oncologists. Ideally cytotoxic agentsthat have specificity for cancer and tumor cells while not affectingnormal cells would be extremely desirable. Unfortunately, none have beenfound and instead agents that target especially rapidly dividing cells(both tumor and normal) have been used.

Clearly, the development of materials that would target cancer cells dueto some unique specificity for them would be a breakthrough.Alternatively, materials that were cytotoxic to cancer cells whileexerting mild effects on normal cells would be desirable.

Human Immunodeficiency Virus (HIV), the etiological agent for AIDS(acquired immune deficiency syndrome), is a member of the lentiviruses,a subfamily of retroviruses. HIV integrates its genetic information intothe genome of the host. Most importantly, HIV infects and invades cellsof the immune system; it breaks down the body's immune system andrenders the patient susceptible to opportunistic infections andneoplasms. HIV-1 is cytopathic for T4 lymphocytes, cells of the immunesystem that express the cell surface differentiation antigen CD4. Inaddition to CD4+ T cells, the host range of HIV includes cells of themononuclear phagocytic lineage, including blood monocytes, tissuemacrophages, Langerhans cells of the skin and dendritic reticulum cellswithin lymph nodes.

Precursor cells in the bone marrow are released into the blood in animmature circulating form known as monocytes. Monocytes use the bloodstrictly as a transport medium. Once they arrive where they're going tobe used, they leave the blood and complete differentiation intomacrophages. Cells of the monocyte/macrophage lineage are a major targetpopulation for infection with HIV in the body and are thought to providereservoirs of virus for disseminating infection throughout the body. HIVis also neurotropic, capable of infecting monocytes and macrophages inthe central nervous system causing severe neurologic damage. They caninteract and fuse with CD4-bearing T cells, causing T cell depletion andthus contributing to the pathogenesis of AIDS.

Progression from HIV infection to AIDS is primarily determined by theeffects of HIV on the cells that it infects, including CD4+ Tlymphocytes and macrophages. In turn, cell activation, differentiationand proliferation regulate HIV infection and replication in those cells.HIV and other lentiviruses can proliferate in nonproliferating,terminally differentiated macrophages and growth-arrested T lymphocytes.This ability of lentiviruses, including HIV, to replicate innonproliferating cells, particularly in macrophages, is believed to beunique among retroviruses.

Due to the above-mentioned problems in the art, the present inventorshave sought improvements and provide such improvements herein.

Carbendazim, or 2-methoxycarbonylaminobenzimidazole, has been studied asa cancer treatment. See U.S. Pat No. 5,767,138 issued Jun. 16, 1998 toJ. B. Camden. Carbendazim metabolizes in the body through thehydroxylation of the benzene ring, primarily in the 5-position. Themetabolite is not as active in the treatment of cancer as the2-methoxycarbonylaminobenzimidazole. Moreover, this compound is not verysoluble. A derivative that maintains the activity of the benzimidazolebut is more soluble is highly preferred. It has been found thatsubstituted benzimidazole carbamates, and in particular, those claimedherein are more soluble, yet maintain cytotoxic behavior.

SUMMARY OF THE INVENTION

The compounds of the present invention are represented by the followingformula A:

wherein,

R is hydrogen, —COOR₂ or —CONHR₂;

R₁ is hydrogen, —COOR₃ or —CONHR₃;

each of R₂ and R₃ is independently alkyl, haloalkyl, alkenyl,haloalkenyl, cycloalkyl, cycloalkalkyl, heterocycloalkyl,heterocycloalkalkyl, substituted or unsubstituted benzyl, hydroxyalkyl,alkoxyalkyl, poly(alkoxy)alkyl, hydroxyalkoxyalkyl,hydroxypoly(alkoxy)alkyl, haloalkoxyalkyl, halopoly(alkoxy)alkyl, oraminoalkyl;

each of X and Y is independently hydrogen, alkyl, alkenyl, cycloalkyl,haloalkyl, haloalkenyl, bromo, chloro, fluoro, nitro, or amino; and

n is 1, 2 or 3.

The benzyl group may optionally be substituted with one or more nitro,carboxy, hydroxy, alkyl, alkoxy, or halide substituents.

Pharmaceutically acceptable salts of the benzimidazole derivatives offormula A are also included in the present invention. Further includedin the invention are the prodrugs of the compounds of formula A.

In one presently preferred embodiment of the invention, thebenzimidazole derivatives of the invention are of the formula A-1 orA-2:

and more preferably the compounds are of formula A-1 or A-2 where eachof X and Y is hydrogen.

In another presently preferred embodiment of the invention, thebenzimidazole derivatives are of the formula A-3:

and more preferably, the compounds are of formula A-3 where X ishydrogen and Y is hydrogen or halogen; the halogen is preferably chloro.

In another presently preferred embodiment of the invention, thebenzimidazole derivatives are of the formula A4:

and more preferably, the compounds are of formula A-4 where X ishydrogen and Y is hydrogen or halogen; the halogen is preferably chloro.

Methods are provided by the present invention for treatment of warmblooded animals, and in particular, humans and other mammals, that areaffected by cancer or viral infection, the methods comprisingadministering a therapeutically effective amount of a benzimidazolederivative of formula A, or a salt or a prodrug thereof, to the animal.

DETAILED DESCRIPTION OF THE INVENTION

A. Definitions

The term “alkyl” refers to a fully saturated monovalent hydrocarbonradical of 1 to 12 carbon atoms. It may be straight-chain or branched.Preferred are those alkyl groups containing 1 to 10 carbon atoms, with 2to 8 carbon atoms particularly preferred.

The term “alkenyl” refers to an unsaturated monovalent hydrocarbonradical of 2 to 12 carbon atoms containing only carbon and hydrogen andhaving one or more double bonds. It may be straight-chain or branched.Preferred are those alkenyl groups containing 2 to 10 carbon atoms, with2 to 8 carbon atoms particularly preferred.

The term “alkoxy” means the group —OR′ wherein R′ is alkyl. Preferredare alkoxy groups having 1 to 10 carbon atoms, more preferably 2 to 8carbon atoms.

The term “alkoxyalkyl” refers to an alkoxy group covalently attached toan alkyl group. The alkoxy group contains from 1 to 12, preferably from1 to 6 carbon atoms. The alkoxy group may be substituted with one ormore hydroxyl groups (an “hydroxyalkoxyalkyl”) or with one or morehalogen atoms (a “haloalkoxyalkyl”); preferably the hydroxyl or halogenis on the terminal end of the alkoxyalkyl substituent.

The term “poly(alkoxy)alkyl” denotes 2 to 200, preferably 2 to 20,alkoxy groups covalently linked in either a linear or a branchedconfiguration and attached to an alkyl group. Linear poly(alkoxy)alkylmoieties have a structure such as

—(CH₂)_(m)—O—(CH₂)_(m)—O—(CH₂)_(m)—O—(CH₂)_(m)— . . . —O—C_(m)H_(2m+1),where “m” is an integer, the same or different along the length of thechain. Branched moieties have two or more (—O—(CH_(t))_(m)—) groupsbound to a common third (—O—(CH_(t))_(m)—) group, where “t” has a valuethat is independently selected from 0, 1 and 2 for each (CH_(t))_(m)group. Linear configurations are preferred. The number of repeating(—O—(CH_(t))_(m)—) groups within a substituent may be up to 200,preferably from 2 to 20, more preferably from 2 to 7, and mostpreferably is 2-5. The individual alkoxy groups may be the same ordifferent, and individual alkoxy groups preferably contain from 1 to 6carbon atoms each, and most preferably from 1 to 3 carbon atoms each. Apresently preferred poly(alkoxy)alkyl is —(CH₂)_(y)—(OCH₂CH₂)_(x)—OCH₃or

—(CH₂)_(y)—(OCH₂CH₂)_(x)—OCH₂CH₃, where y=1-4 and x=1-100, preferably1-10, and more preferably, 2-5. The individual alkoxy groups may besubstituted with one or more hydroxyl groups (an“hydroxypoly(alkoxy)alkyl”) or with one or more halogen atoms (a“halopoly(alkoxy)alkyl”); preferably the hydroxyl or halogen is on theterminal end of the poly(alkoxy)alkyl substituent.

“Heterocyclo” designates a heterocyclic group; that is, a closed-ringstructure, usually of either 5 or 6 members, in which one or more of theatoms in the ring is an element other than carbon, such as for examplesulfur, nitrogen, or oxygen. A heterocyclic group may be, but is notlimited to, pyridine, pyrrole, furan, thiophene, morpholine, and purine,optionally substituted with one or more nitro, carboxy, sulfonic acid,hydroxy, alkyl, alkoxy, or halide substituents.

The term “amino” refers to primary amines (—NH₂), secondary amines(—NHR′), and tertiary amines (—NR′R″), where R′ and R″ are the same ordifferent substituent groups, such as alkyl, alkenyl, halogen, hydroxy,and the like.

“Independently” signifies that two or more of the groups immediatelypreceding the term are either identical or different; i.e., selection ofone from the list following the term does not affect selection of theother(s).

“Substituted” encompasses both single and multiple substitutions, thelatter including multiple substitutions by the same substituent as wellas mixtures of different substituents.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances in which said event or circumstanceoccurs and instances in which it does not. For example, “optionallysubstituted phenyl” means that the phenyl may or may not be substitutedand that the description includes both unsubstituted phenyl and phenylwherein there is substitution. As another example, “optionally” followedby “converting the free base to the acid addition salt” means that suchconversion may or may not be carried out in order for the processdescribed to fall within the invention, and the invention includes thoseprocesses wherein the free base is converted to the acid addition saltand those processes in which it is not.

As used herein, “a therapeutically effective amount” means theconcentration or quantity or level of the compound of the presentinvention that can attain a particular medical end, such as control ordestruction of cancer cells, virally-infected cells, or viruses withoutproducing unacceptable toxic symptoms. The term “safe and effectiveamount” refers to the quantity of a component which is sufficient toyield a desired therapeutic response without undue adverse side effects(such as toxicity, irritation, or allergic response) commensurate with areasonable benefit/risk ratio when used in the manner of this invention.The specific “safe and effective amount” will vary with such factors asthe particular condition being treated, the physical condition of thepatient, the type of mammal being treated, the duration of thetreatment, the nature of concurrent therapy (if any), and the specificformulations employed and the structure of the compounds or its salts.

As used herein, a “pharmaceutical addition salt” or “pharmaceuticallyacceptable salt” is a salt of the benzimidazole derivative compound withan organic or inorganic acid. These preferred acid addition salts arechlorides, bromides, sulfates, nitrates, phosphates, sulfonates,formates, tartrates, maleates, malates, citrates, benzoates,salicylates, ascorbates, and others known to those of ordinary skill inthe art.

As used herein, the term “prodrug” refers to a form of a benzimidazolederivative compound that has minimal therapeutic activity until it isconverted to its desired biologically active form. A prodrug is acompound having one or more functional groups or carriers covalentlybound thereto, which functional groups or carriers are removed from thecompound by metabolic processes within the body to form the respectivebioactive compound.

As used herein, the term “metabolite” refers to the break-down or endproduct of a benzimidazole derivative compound or its salt produced bymetabolism or biotransformation in the animal or human body; e.g.,biotransformation to a more polar molecule such as by oxidation,reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman,“The Pharmacological Basis of Therapeutics” 8^(th) Ed., Pergamon Press,Gilman et al. (eds.), 1990 for a discussion of biotransformation). Asused herein, the metabolite of a benzimidazole derivative compound orits salt may be the biologically active form of the compound in thebody. An assay for activity of a metabolite of a benzimidazolederivative of the present invention is known to one of skill in the artin light of the present disclosure, for example, testing for efficacyagainst a virus in vitro or in vivo.

As used herein, a “subject in need thereof” is a warm blooded animalhaving cancer or having a viral infection.

As used herein, “cancer” refers to all types of cancers, or neoplasms orbenign or malignant tumors. In one embodiment, those cancers that attacknormal healthy blood cells or bone marrow are contemplated by thepresent invention. Preferred cancers for treatment using methodsprovided herein include carcinoma, sarcoma, lymphoma, or leukemia. By“carcinoma” is meant a benign or malignant epithelial tumor andincludes, but is not limited to, breast carcinoma, prostate carcinoma,non-small cell lung carcinoma, colon carcinoma, CNS carcinoma, melanomacarcinoma, ovarian carcinoma, or renal carcinoma. A preferred host is ahuman host.

A “viral infection” as used herein means an infection due to a DNA virusor an RNA virus (retrovirus). Examples of a double-stranded DNA virusare the Herpes virus and the influenza virus. Human immunodeficiencyvirus (HIV) is a prototype for retroviruses, i.e., viruses that usereverse transcription to replicate. However, certain DNA viruses use, inpart, reverse transcription mechanisms to replicate such as, forexample, the Hepatitus B virus. “Viruses” include retroviruses such asHIV or HTLV, influenza, rhinoviruses, herpes, hepatitis, or the like.

As used herein, a benzimidazole derivative of formulas A and A-1 throughA-4, or a pharmaceutical salt thereof or a prodrug thereof, are“compounds of the present invention.” Such compounds are further setforth under B infra.

As used herein, “chemotherapeutic agents” includes DNA-interactiveagents, antimetabolites, tubulin-interactive agents, hormonal agents andothers, such as asparaginase or hydroxyurea, and are as further setforth under D infra.

As used herein, “potentiators” are materials that affect the immunesystem or enhance the effectiveness of a compound of the presentinvention and are further set forth under E herein.

Following long-standing patent law convention, the terms “a” and “an”mean “one or more” when used in this application, including the claims.

B. Benzimidazole Derivatives

The benzimidazole derivatives of the present invention are those offormula A, as set forth above. In one embodiment of the invention,presently preferred compounds are those of formulas A-1 and A-2. Inanother embodiment, presently preferred compounds are those of formulasA-3 and A-4.

Pharmaceutically acceptable salts of the benzimidazole compounds areconsidered within the scope of compounds of the present invention. Theyare salts with an organic or inorganic acid. Preferred acid additionsalts are chlorides, bromides, sulfates, nitrates, phosphates,sulfonates, formates, tartrates, maleates, malates, citrates, benzoates,salicylates, ascorbates, or the like. Such salts may be synthesized fromthe compound of the present invention, or derivative thereof, thatcontains a basic or acidic moiety, by conventional chemical methods.Generally, such salts may be prepared by reacting a free acid or baseform of the compound, or derivative thereof, with a stoichiometricamount of the appropriate base or acid in water or in an organicsolvent, or in a mixture of the two. Generally, nonaqueous media likeether, ethyl acetate, ethanol, isopropanol, or acetonitrile arepreferred. Further suitable salts may be found in Remington: The Scienceand Practice of Pharmacy, 19th ed., Mack Publishing Company, Easton,Pa., 1995, p. 1457.

Pharmaceutically acceptable salts of the compounds of the presentinvention include conventional non-toxic salts or the quaternaryammonium salts of the compounds or derivatives formed, for example, fromnon-toxic inorganic or organic acids. For example, such conventionalnon-toxic salts include those derived from inorganic acids such ashydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, orthe like; and salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, or the like.Preferred acid addition salts are chlorides, bromides, sulfates,nitrates, phosphates, sulfonates, formates, tartrates, maleates,malates, citrates, benzoates, salicylates, ascorbates, or the like. Apresently preferred salt is the hydrochloride salt.

Further included within the scope of the compound, or salts thereof,useful for the present invention are prodrugs thereof. As used herein, a“prodrug” is a drug covalently bonded to a carrier wherein release ofthe drug occurs in vivo when the prodrug is administered to a mammaliansubject. Prodrugs of the compounds of the present invention are preparedby modifying functional groups present in the compounds in such a waythat the modifications are cleaved, either in routine manipulation or invivo, to yield the desired compound. Prodrugs include compounds whereinhydroxy, amine, or sulfhydryl groups are bonded to any group that, whenadministered to a mammalian subject, is cleaved to form a free hydroxyl,amino, or sulfhydryl group, respectively. Examples of prodrugs include,but are not limited to, acetate, formate, or benzoate derivatives ofalcohol or amine functional groups in the compounds of the presentinvention; phosphate esters, dimethylglycine esters, aminoalkylbenzylesters, aminoalkyl esters or carboxyalkyl esters of alcohol or phenolfunctional groups in the compounds of the present invention; or thelike.

Synthetic Reaction Parameters

The terms “solvent”, “inert organic solvent” and “inert solvent” mean asolvent that is passive or non-reactive under the conditions of thereaction being described in conjunction therewith (including, forexample, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”),dimethylformamide (“DMF”), chloroform, methylene chloride (ordichloromethane), diethyl ether, methanol, pyridine, and the like).Unless specified to the contrary, the solvents used in the reactions ofthe present invention are inert organic solvents.

The reaction temperature can vary widely depending on the reactivity ofthe reactants. However, the temperature should not be so high as todecompose the reactants or so low as to cause inhibition of thecondensation or freezing of the solvent. Unless specified to thecontrary, the reactions described herein take place at atmosphericpressure over a temperature range from the temperature of dry ice toabout 100° C., more preferably from about 10° C. to about 50° C., andmost preferably at “room” or “ambient” temperature (“RT”), e.g. about20° C.

Unless otherwise specified, the reaction times and conditions areintended to be approximate.

The time required for the reactions herein will depend to a large extenton the temperature being used and the relative reactivities of thestarting materials. Therefore, the reaction time can vary greatly, forexample from about five minutes to about two days. Various knowntechniques such as different types of chromatography, especially thinlayer chromatography (“TLC”), gas chromatography (“GC”), or spectroscopycan be used to follow the progress of the reaction by the disappearanceof the starting compound(s).

Isolation and purification of the compounds and intermediates describedherein can be effected, if desired, by any suitable separation orpurification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography,thick-layer chromatography, centrifugal chromatography, or preparatoryHPLC, or a combination of these procedures. Specific illustrations ofsuitable separation and isolation procedures can be found by referenceto the examples hereinbelow. However, other equivalent separation orisolation procedures can, of course, also be used.

Synthesis of Compounds of Formula A

The compounds of the invention are prepared by modification to thebenzimidazole nucleus:

In one synthetic process, commercially available 2-aminobenzimidazole(101) can be reacted with a variety of chloroformates or isocyanates inpyridine to form, respectively, carbamates (105) or ureas (103) at theN3 position. In this manner, N3-substituted benzimidazole derivatives offormula A-1 (105) or A-2 (103) with a free 2-amino group are synthesized(Reaction Scheme 1).

By heating the N3-acyl analogs (103, 105) in pyridine, the acyl groupscan be induced to migrate to the 2-amino position to give benzimidazolederivatives of formula A-3 or A-4 (205 and 203, respectively) (ReactionScheme 2).

Where it is desired to synthesize a compound of formula A having achlorine atom at the 5(6) position, 4-chloro-1,2-phenylenediamine 301 iscondensed with cyanogen bromide (Zou, R. et al., J. Med. Chem.40:811-818 (1997)) to give the corresponding chloro 2-aminobenzimidazole303. The benzimidazole 303 can then be heated with an isocyanate inpyridine to form the chloro 2-aminourea analogs 305 (Reaction Scheme 3).

In another method for preparing the compounds of formula A-3 or A-4, thecommercially-available fungicide methyl 2-aminobenzimidazole carbamate(carbendazim, 401) is treated with an appropriate alcohol or amine withor without added toluene as the solvent in the presence of aluminumisopropoxide catalyst to give new carbamates (403) and ureas (405),respectively (Reaction Scheme 4).

Presently Preferred Embodiments

In one embodiment of the present invention, presently preferredbenzimidazole derivatives are those where R₁ and X are hydrogen, and Yis hydrogen or chloro and is in the 5(6)-position. Further preferred arethose compounds where R₁, X and Y are hydrogen and R is selected fromthose groups listed in Table 1: Solubility is based on a standardmeasure used in medicinal chemistry, the octanol-water partitioncoefficient, LogP, Lower Log) values indicate higher aqueous solubility.There are a variety of methods to estimate this value for a proposedstructure using computer calculations. The below LogP solubility valueswere determined using the atom typing method of Ghose, Pritchett et al.(J. Comput. Chem 9(1): 80-90, 1988). Carbendazim has a LogP of 1.302.

TABLE 1 Cpd. No. R LogP 1-1 —COOCH₂CH═CH₂ 2.408 1-2 —COOCH₂CCl₃ 3.2021-3 —CONHCH₂CH₂Cl 1.721 1-4 —CONHCH₂Ph 2.794 1-5 —COOCH₂Ph 3.444 1-6—CONHCH₂CH₂CH₂ 1.829 1-7 —COOCH₂CH₂CH₃ 2.479 1-8 —COOCH₂CH₂CH₇N(CH₃)₂ —1-9 —CONHCH₂Ph(-2-OH) — 1-10 —COOCH,CH₂-morpholino — 1-11—COOCH(CH₃)(cyclopropyl) —

In another embodiment of the invention, presently preferredbenzimidazole derivatives are those where R is hydrogen, X is hydrogen,and Y is hydrogen or chloro and is in the 5(6)-position. Furtherpreferred are those compounds where R and X are hydrogen, Y is hydrogenor chloro in the 5(6) position, and R₁ is selected from those groupslisted in Table 2:

TABLE 2 Cpd. No. R₁ LogP 2-1 —CONHCH₂CH₂,N(CH₃)₂ 0.631 2-2 —COOCH₂CH═CH₂2.042 2-3 —COO(CH₂CH₂O)₂CH₂CH₃ 1.315 2-4 —CONHCH₂CH₂OCH₂CH₂OH 0.044 2-5—COOCH₂CH₂OCH₂CH₂Cl 1.841 2-6 —COOCH₂CH₂Cl 2.005 2-7 —COOCH₂CH₂OCH₂CH₂OH0.694 2-8 —COOCH₂CH₂CH₃ 2.113 2-9 —COOCH₂Ph 3.078 2-10 —CONHCH₂CH₂Cl1.355 2-10* —CONHCH₂CH₂Cl 1.873 2-11 —CONHCH₂Ph 2.428 2-12—CONHCH₂CH₂CH₃ 1.463 2-12* —CONHCH₂CH₂CH₃ 1.981 2-13 —CONHCH₃ — 2-13*—CONHCH₃ 1.170 2-14 —CONHCH₂Ph(-2-OH) — 2-15 —COOCH₂CH₂-morpholino —2-16 —COOCH(CH)(cyclopropyl) —

C. Screening Assays

Screening assays for determining those cancers susceptible to treatmentusing compounds of the present invention include incubating cell linemodels representing specific cancers as set forth, for example, by theNational Cancer Institute, in the presence and absence of suchcompounds. Viability of cells may be determined by the MTT assay(Promega Corp., Madison, Wis. 53711), or the SRB (sulforhodamine B)assay (Skehan, et al., JNCI, 82:13,1107,1990). Susceptibility to saidcompounds exists when viability in the presence of a compound of thepresent invention is less than viability in the absence of suchcompound.

Exemplary cell line models representing specific cancers include, butare not limited to, the following:

Non-small cell lung cancer: NCIH23, NCIH324, NCIH522, A549/ATCC,A549(ASC), CALU1, EKVX, NCIH125M, NCIH226, NCIH520, SKMES1, NCIH322M,NCIH358M, NCIH460, NCIH292, HOP62, HOP18, HOP19, HOP92, LXFL 529,SW1573, LXFS 650L, ML1019, ML1076, ML1045, or UABLG22;

Small cell lung cancer: NCIH69, NCIH146, NCIH82, NCIH524, DMS 114, DMS273, HOP27, SHP77, or RHOS;

Colon cancer: HT29, HCC2998, HCT116, LOVO, SW1116, SW620, COLO 205,DLD1, WIDR, COLO 320DM, HCT15, CXF 280, KM12, KM20L2, COLO 741, CXF264L, COLO 746, UABC02, MLI059, CAC02, HT29/PAR, HT29/MDR1, or NB4;

Breast cancer: MCF7, MCF7/ADRRES, ZR751, ZR7530, MDAMB231/ATCC, HS 578T,UISOBCA1, MCF7/ATCC, SKBR3, MDAMB435, MDAN, BT549, T47D, MDAMB231, MAXF401, BT474, or MDAMB468;

Ovarian cancer: OVCAR3, OVCAR4, OVCAR5, OVCAR8, A2780, IGROV1, SKOV3,OVXF 899, A1336, or ES2;

Leukemia: P388, P3888/ADR, CCRFCEM, CCRFSB, K562, MOLT4, L1210,HL60(TB), RPMI8226, SR, or K562/ADR;

Fibroblast: IMR90, or CCD19LU;

Renal cancer: UO31, SN12C, SN12S1, SN12K1, SN12L1, SN12A1, A498, A704,CAKI1, RXF 393, RXF631, 7860, SW156, TK164, 769P, SS78, ACHN, TK10, RXF486L, UOK57, or UOK57LN;

Melanoma: LOX IMVI, MALME3M, RPMI7951, SKMEL2, SKMEL5, SKMEL28, SKMEL31,UCSD 242L, UCSD 354L, M14, M19MEL, UACC62, UACC257, MEXF 514L, orUABMEL3;

Prostate cancer: PC3, PC3M, DU145, LNCAP, 1013L, UMSCP1, WIS, JE, RER,MRM, DHM, AG, RB, RVP, FC, WAE, DB/SMC, JCA1, ND1, WMF, TSUPRI, JECA,GDP, T10, WBW, RVP1, or WLL;

CNS cancer: SNB7, SNB 19, SNB44, SNB56, SNB75, SNB78, U251, TE671,SF268, SF295, SF539, XF 498, SW 1088, SW 1783, U87 MG, SF767, SF763,A172, or SMSKCNY;

Bone/muscle: A204/ATCC, OHS, TE85, A673, CHA59, MHM 25, RH18, RH30, orRD; and

Lymphoma: AS283, HT, KD488, PA682, SUDHL7, RL, DB, SUDHL1, SUDHL4,SUDHL10,NUDUL1, or HUT 102.

D. Chemotherapeutic Agents

Chemotherapeutic agents are generally grouped as DNA-interactive agents,antimetabolites, tubulin-interactive agents, hormonal agents, otheragents such as asparaginase or hydroxyurea, and agents as set forth inTable 3. Each of the groups of chemotherapeutic agents can be furtherdivided by type of activity or compound. Chemotherapeutic agents used incombination with a compound of the present invention, or salts thereofof the present invention may be selected from any of these groups butare not limited thereto. For a detailed discussion of thechemotherapeutic agents and their method of administration, see Dorr, etal, Cancer Chemotherapy Handbook, 2d edition, pages 15-34, Appleton &Lange (Connecticut, 1994) herein incorporated by reference.

DNA-interactive agents include alkylating agents, e.g., cisplatin,cyclophosphamide, and altretamine; DNA strand-breakage agents, such asbleomycin; intercalating topoisomerase II inhibitors, e.g., dactinomycinand doxorubicin; nonintercalating topoisomerase II inhibitors, such asetoposide and teniposide; and the DNA minor groove binder plicamycin,for example.

The alkylating agents form covalent chemical adducts with cellular DNA,RNA, or protein molecules, or with smaller amino acids, glutathione, orsimilar chemicals. Generally, alkylating agents react with anucleophilic atom in a cellular constituent, such as an amino, carboxyl,phosphate, or sulfhydryl group in nucleic acids, proteins, amino acids,or in glutathione. The mechanism and the role of these alkylating agentsin cancer therapy is not well understood.

Typical alkylating agents include, but are not limited to, nitrogenmustards, such as chlorambucil, cyclophosphamide, isofamide,mechlorethamine, melphalan, uracil mustard; aziridine such as thiotepa;methanesulphonate esters such as busulfan; nitroso ureas, such ascarmustine, lomustine, streptozocin; platinum complexes, such ascisplatin, carboplatin; bioreductive alkylator, such as mitomycin, andprocarbazine, dacarbazine and altretamine.

DNA strand breaking agents include bleomycin, for example.

DNA topoisomerase II inhibitors include the following intercalators,such as amsacrine, dactinomycin, daunorubicin, doxorubicin (adriamycin),idarubicin, and mitoxantrone; nonintercalators, such as etoposide andteniposide, for example.

A DNA minor groove binder is plicamycin, for example.

Antimetabolites interfere with the production of nucleic acids by one oftwo major mechanisms. Certain drugs inhibit production ofdeoxyribonucleoside triphosphates that are the immediate precursors forDNA synthesis, thus inhibiting DNA replication. Certain of the compoundsare analogues of purines or pyrimidines and are incorporated in anabolicnucleotide pathways. These analogues are then substituted into DNA orRNA instead of their normal counterparts.

Antimetabolites useful herein include, but are not limited to, folateantagonists such as methotrexate and trimetrexate; pyrimidineantagonists, such as fluorouracil, fluorodeoxyuridine, CB3717,azacitidine, cytarabine, and floxuridine; purine antagonists includemercaptopurine, 6-thioguanine, fludarabine, pentostatin; andribonucleotide reductase inhibitors include hydroxyurea.

Tubulin interactive agents act by binding to specific sites on tubulin,a protein that polymerizes to form cellular microtubules. Microtubulesare critical cell structure units. When the interactive agents bind theprotein, the cell can not form microtubules. Tubulin interactive agentsinclude vincristine and vinblastine, both alkaloids and paclitaxel(Taxol), for example.

Hormonal agents are also useful in the treatment of cancers and tumors.They are used in hormonally susceptible tumors and are usually derivedfrom natural sources. Hormonal agents include, but are not limited to,estrogens, conjugated estrogens and ethinyl estradiol anddiethylstilbesterol, chlortrianisen and idenestrol; progestins such ashydroxyprogesterone caproate, medroxyprogesterone, and megestrol; andandrogens such as testosterone, testosterone propionate;fluoxymesterone, and methyltestosterone.

Adrenal corticosteroids are derived from natural adrenal cortisol orhydrocortisone. They are used because of their anti-inflammatorybenefits as well as the ability of some to inhibit mitotic divisions andto halt DNA synthesis. These compounds include, but are not limited to,prednisone, dexamethasone, methylprednisolone, and prednisolone.

Leutinizing hormone releasing hormone agents or gonadotropin-releasinghormone antagonists are used primarily the treatment of prostate cancer.These include leuprolide acetate and goserelin acetate. They prevent thebiosynthesis of steroids in the testes.

Antihormonal antigens include, for example, antiestrogenic agents suchas tamoxifen, antiandrogen agents such as flutamide; and antiadrenalagents such as mitotane and aminoglutethimide.

Further agents include the following: hydroxyurea appears to actprimarily through inhibition of the enzyme ribonucleotide reductase, andasparaginase is an enzyme which converts asparagine to nonfunctionalaspartic acid and thus blocks protein synthesis in the tumor.

Taxol (paclitaxel) is a preferred chemotherapeutic agent.

A listing of currently available chemotherapeutic agents according toclass, and including diseases for which the agents are indicated, isprovided as Table 3.

TABLE 3 Neoplastic Diseases¹ for which Exemplary Chemotherapeutic agentsare Indicated Class Type of Agent Name Disease² Alkylating AgentsNitrogen Mustards Mechlorethamine Hodgkin's disease, non-Hodgkin'slymphomas (HN₂) Cyclophosphamide Ifosfamide Acute and chroniclymphocytic leukemias, Hodgkin's disease, non-Hodgkin's lymphomas,multiple myeloma, neuroblastoma, breast, ovary, lung, Wilms' tumor,cervix, testis, soft-tissue sarcomas Melphalan Multiple myeloma, breast,ovary Chlorambucil Chronic lymphocytic leukemia, primarymacroglobulinemia, Hodgkin's disease, non-Hodgkin's lymphomasEstramustine Prostate Ethylenimines and Hexamethylmelamine OvaryMethylmelamines Thiotepa Bladder, breast, ovary Alkyl SulfonatesBusulfan Chronic granulocytic leukemia Nitrosoureas Carmustine Hodgkin'sdisease, non-Hodgkin's lymphomas, primary brain tumors, multiplemyeloma, malignant melanoma Lomustine Hodgkin's disease, non-Hodgkin'slymphomas, primary brain tumors, small-cell lung Semustine Primary braintumors, stomach, colon Streptozocin Malignant pancreatic insulinoma,malignant carcinoid Triazenes Dacarbazine Malignant melanoma, Hodgkin'sdisease, soft-tissue sarcomas Procarbazine Aziridine AntimetabolitesFolic Acid Analogs Methotrexate Trimetrexate Acute lymphocytic leukemia,choriocarcinoma, mycosis fungoides, breast, head and neck, lung,osteogenic sarcoma Pyrimidine Analogs Fluorouracil Breast, colon,stomach, pancreas, ovary, head and neck, Floxuridine urinary bladder,premalignant skin lesions (topical) Cytarabine Azacitidine Acutegranulocytic and acute lymphocytic leukemias Purine Analogs and RelatedMercaptopurine Acute lymphocytic, acute granulocytic, and chronicInhibitors granulocytic leukemias Thioguanine Acute granulocytic, acutelymphocytic, and chronic granulocytic leukemias Pentostatin Hairy cellleukemia, mycosis fungoides, chronic lymphocytic leukemia FludarabineChronic lymphocytic leukemia, Hodgkin's and non-Hodgkin's lymphomas,mycosis fungoides Natural Products Vinca Alkaloids Vinblastine (VLB)Hodgkin's disease, non-Hodgkin's lymphomas, breast, testis VincristineAcute lymphocytic leukemia, neuroblastoma, Wilms' tumor,rhabdomyosarcoma, Hodgkin's disease, non-Hodgkin's lymphomas, small-celllung Vindesine Vinca-resistant acute lymphocytic leukemia, chronicmyelocytic leukemia, melanoma, lymphomas, breast EpipodophyllotoxinsEtoposide Testis, small-cell lung and other lung, breast, Hodgkin'sTeniposide disease, non-Hodgkin's lymphomas, acute granulocyticleukemia, Kaposi's sarcoma Antibiotics Dactinomycin Choriocarcinoma,Wilms' tumor, rhabdomyosarcoma, testis, Kaposi's sarcoma DaunorubicinAcute granulocytic and acute lymphocytic leukemias DoxorubicinSoft-tissue, osteogenic, and other sarcomas; Hodgkin's disease,4′-Deoxydoxorubicin non-Hodgkin's lymphomas, acute leukemias, breast,genitourinary, thyroid, lung, stomach, neuroblastoma Bleomycin Testis,head and neck, skin, esophagus, lung, and genitourinary tract; Hodgkin'sdisease, non-Hodgkin's lymphomas Plicamycin Testis, malignanthypercalcemia Mitomycin Stomach, cervix, colon, breast, pancreas,bladder, head and neck Enzymes L-Asparaginase Acute lymphocytic leukemiaTaxanes Docetaxel Breast, ovarian Taxoids Paclitaxel Biological ResponseInterferon Alfa Hairy cell leukemia, Kaposi's sarcoma, melanoma,carcinoid, Modifiers renal cell, ovary, bladder, non-Hodgkin'slymphomas, mycosis fungoides, multiple myeloma, chronic granulocyticleukemia Tumor Necrosis Factor Investigational Tumor-InfiltratingInvestigational Lymphocytes Miscellaneous Agents Platinum CoordinationCisplatin Testis, ovary, bladder, head and neck, lung, thyroid, cervix,Complexes Carboplatin endometrium, neuroblastoma, osteogenic sarcomaAnthracenedione Mitoxantrone Acute granulocytic leukemia, breastSubstituted Urea Hydroxyurea Chronic granulocytic leukemia, polycythemiavera, essential thrombocytosis, malignant melanoma Methyl HydrazineProcarbazine Hodgkin's disease Derivative Adrenocortical SuppressantMitotane Adrenal cortex Aminoglutethimide Breast Hormones andAdrenocorti-costeroids Prednisone Acute and chronic lymphocyticleukemias, non-Hodgkin's Antagonists lymphomas, Hodgkin's disease,breast Progestins Hydroxy-progesterone caproate Endometrium, breastMedroxy-progesterone acetate Megestrol acetate EstrogensDiethylstil-bestrol Breast, prostate Ethinyl estradiol AntiestrogenTamoxifen Breast Androgens Testosterone Breast propionateFluoxymesterone Antiandrogen Flutamide Prostate Gonadotropin- LeuprolideProstate, Estrogen-receptor-positive breast releasing hormone analogGoserelin ¹Adapted from Calabresi, P., and B. A. Chabner, “Chemotherapyof Neoplastic Diseases” Section XII, pp 1202-1263 in: Goodman andGilman's The Pharmacological Basis of Therapeutics, Eighth ed., 1990Pergamin Press, Inc.; and Barrows, L. R., “Antineoplastic andImmunoactive Drugs”, Chapter 75, pp 1236-1262, in: Remington: TheScience and Practice of Pharmacy, Mack Publishing Co. Easton, PA, 1995.;both references are incorporated by reference herein, # in particularfor treatment protocols. ²Neoplasms are carcinomas unless otherwiseindicated.

E. Potentiators

A “potentiator,” as used herein, is a material that improves orincreases the efficacy of the benzimidazole derivatives or a salt or aprodrug thereof, or that acts on the immune system as animmunomodulator. Potentiators can be used in combination with a compoundof the present invention. A potentiator may be an antiviral agent. Onesuch potentiator is triprolidine or its cis-isomer. Triprolidine isdescribed in U.S. Pat. No. 5,114,951 (1992, the patent is incorporatedby reference herein). A further potentiator is procodazole, (also named1H-benzimidazole-2-propanoic acid, or β-(2-benzimidazole) propionic acidor 2-(2-carboxyethyl)benzimidazole or propazol). Procodazole is anon-specific immunoprotective agent active against viral and bacterialinfections and may be used in combination with the compounds set forthherein. Procodazole is effective with a compound of the presentinvention, alone in treating cancers, tumors, leukemia or viralinfections, or combined with a chemotherapeutic agent.

Further potentiators include, but are not limited to, propionic acid,salts thereof, or esters thereof, antioxidant vitamins such as vitaminsA, C, E, or beta-carotene; abacavir; AL-721 (lipid mixture); amprenavir;Amphotericin B methyl ester; Ampligen (mismatched RNA); anti-AIDSantibody; anti-human interferon-α antibody; anti-AIDS antibody, ascorbicacid and derivatives thereof, AS-101 (heavy metal basedimmunostimulant); azidothymidine; β-interferon; Bropirimine; butylatedhydroxytoluene; Ciamexon, Cimetidine; CL-246,738, colony stimulatingfactors, including GM-CSF; Creme Pharmatex (benzalkonium chloride);CS-82 (5-unsubstituted derivative of Zidovudine); Cyclosporin;D-penicillamine (3-mercapto-D-valine); delavirdine; dextran sulphate;dinitrochlorobenzene; efavirenz; erythropoietin; Foscarnet (trisodiumphosphonoformate); fusidic acid; ganciclovir; glucan; glycyrrhizin,HPA-23 (ammonium-21-tungsto-9-antimonate); human immunevirus antiviral;hyperimmune gamma-globulin, IMREG-1, IMREG-2; indinavir; interferon-α;interferon-gamma; interleukin-1 or interleukin-2; isoprinosine; Krestin;LC-9018; lamivudine; lentilart; LF-1695; methionine-enkephalin;Minophagen C; muramyl tripeptide; naltrexone; nelfinavir; Neutropin;nevirapine; Nonoxinol; Ornidyl (eflornithine); non-nucleoside inhibitorsof reverse transcriptase; nucleoside analogues (ddA, ddC, ddI, ddT, ddG,AZT, and the like); pentamidine isethionate; Phenytoin;polymannoacetate; Peptide T (octapeptide sequence); protease inhibitors;Ribavirin; Rifabutin (ansamycin); ritonavir; RNA immunomodulator; rsT4(recombinant soluble T4); saquinavir; shosaikoto and ginseng; SK-818(germanium-derived antiviral); sodium diethylthiocarbamate; stavudine;stearic acid derivative; suramin and analogues thereof, thymic humoralfactor; TP-5; Thymosin fraction 5 and Thymosin 1; Thymostimulin; TNF(tumor necrosis factor), vitamin B preparations; Trimetrexate; UA001;alpha-interferon; or acyclovir, for example.

A compound, or a salt or a prodrug thereof, of the present invention maybe combined with a potentiator and with a chemotherapeutic agent in themethods of the present invention.

F. Dosage

Any suitable dosage may be administered in the methods of the presentinvention. The compound or salt or prodrug thereof chosen for aparticular application, the carrier and the amount will vary widelydepending on the species of the warm blooded animal or human, the typeof cancer, or the particular viral infection being treated, anddepending upon the effective inhibitory concentrations observed in trialstudies. The dosage administered will, of course, vary depending uponknown factors, such as the pharmacodynamic characteristics of theparticular compound, salt, or combination and its mode and route ofadministration; the age, health, or weight of the subject; the natureand extent of symptoms; the metabolic characteristics of the drug andpatient, the kind of concurrent treatment; the frequency of treatment;or the effect desired.

Generally a dosage of as little as about 1-2 milligram (mg) per kilogram(kg) of body weight is suitable, but preferably as little as 10 mg/kgand up to about 10,000 mg/kg may be used. Preferably, a dosage from 15mg/kg to about 5000 mg/kg is used. Most preferably, the dose is between150 mg/kg to about 1000 mg/kg. Doses useful in the treatment of canceror viral infections are 250 mg/kg, 500 mg/kg, 800 mg/kg, 1000 mg/kg,1500 mg/kg, 2500 mg/kg, 3500 mg/kg, 4000 mg/kg, 5000 mg/kg, or 6000mg/kg. Any range of doses can be used. Generally, a compound, saltthereof, prodrug thereof, or combination of the present invention can beadministered on a daily basis one or more times a day, or one to fourtimes a week, either in a single dose or separate doses during the day.Twice-weekly dosing over a period of at least several weeks ispreferred, and often dosing will be continued over extended periods oftime and possibly for the lifetime of the patient. However, the dosageand the dosage regimen will vary depending on the ability of the patientto sustain the desired and effective plasma levels of the compounds ofthe present invention, or salt or prodrug thereof, in the blood.

The compound, salt thereof, prodrug thereof, or combination may bemicronized or powdered so that it is more easily dispersed andsolubilized by the body. Processes for grinding or pulverizing drugs arewell known in the art. For example, a hammer mill or similar millingdevice can be used. The preferred particle size is less than about 100μand preferably less than 50μ.

Intravenously, the most preferred doses may range from about 1 to about10 mg/kg/minute during a constant rate infusion.

The dosage for humans is generally less than that used in mice and istypically about {fraction (1/12)} of the dose that is effective in mice.Thus, if 500 mg/kg was effective in mice, a dose of 42 mg/kg would beused in humans. For a 60 kg man, this dose would be 2520 mg.

The compounds and salts and prodrugs thereof of the present inventionare generally safe. The LD₅₀ is high, about 1500 mg/kg given orally inmice and there are no special handling requirements. The compounds canbe given orally, and since they are not very soluble, they arepreferably given in tablet form or as a suspension. Alternatively, whenmicronized to sufficiently small size, they may be and preferably aregiven as an injection.

The compounds and salts and prodrugs thereof of the present inventionmay be administered in a unit dosage form which may be prepared by anymethods known to one of skill in the art in light of the presentdisclosure. Unit dosages may include from I milligram to 1000 milligramsof active ingredient. Preferably the dosage unit will contain from about10 mg to about 500 mg active ingredient. The active ingredient isgenerally present in an amount of about 0.5% to about 95% by weightbased on the total weight of the dosage unit.

For intravenous use, preferred dosages may range from about 1 to about10 mg/kg/minute during a constant rate infusion.

A dosage unit may comprise a single compound, or mixtures thereof, withother compounds or other cancer- or viral-inhibiting compounds. Thedosage unit may comprise diluents, extenders, carriers, liposomes, orthe like. The unit may be in solid or gel form such as pills, tablets,capsules and the like or in liquid form suitable for oral, rectal,topical, intravenous injection or parenteral administration or injectioninto or around the treatment site. The range and ratio of benzimidazolederivative, or salt or prodrug thereof, to chemotherapeutic agent or topotentiator will depend on the type of cancer or viral infection beingtreated and the particular chemotherapeutic agent or potentiator.

G. Formulations

Formulations of the present invention include the compound of thepresent invention, a salt thereof or a prodrug thereof and, optionally,a chemotherapeutic agent and, optionally, a potentiator, generally mixedwith a pharmaceutically acceptable carrier. A “pharmaceutical carrier”is a pharmaceutically acceptable solvent, suspending agent or vehiclefor delivering a compound of the present invention to the animal orhuman. The carrier may be liquid or solid and is selected with theplanned manner of administration in mind. A “pharmaceuticallyacceptable” component is one that is suitable for use with humans and/oranimals without undue adverse side effects (such as toxicity,irritation, and allergic response) commensurate with a reasonablebenefit/risk ratio.

Oral formulations suitable for use in the practice of the presentinvention include capsules, gels, cachets, tablets, effervescent ornon-effervescent powders or tablets, powders or granules; as a solutionor suspension in aqueous or non-aqueous liquid; or as an oil-in-waterliquid emulsion or a water-in-oil emulsion. The compounds of the presentinvention may also be presented as a bolus, electuary, or paste.

Generally, formulations are prepared by uniformly mixing the activeingredient with liquid carriers or finely divided solid carriers orboth, and then if necessary shaping the product. A pharmaceuticalcarrier is selected on the basis of the chosen route of administrationand standard pharmaceutical practice. Each carrier must be “acceptable”in the sense of being compatible with the other ingredients of theformulation and not injurious to the subject. This carrier can be asolid or liquid and the type is generally chosen based on the type ofadministration being used. Examples of suitable solid carriers includelactose, sucrose, gelatin, agar and bulk powders. Examples of suitableliquid carriers include water, pharmaceutically acceptable fats andoils, alcohols or other organic solvents, including esters, emulsions,syrups or elixirs, suspensions, solutions and/or suspensions, andsolution and or suspensions reconstituted from non-effervescent granulesand effervescent preparations reconstituted from effervescent granules.Such liquid carriers may contain, for example, suitable solvents,preservatives, emulsifying agents, suspending agents, diluents,sweeteners, thickeners, and melting agents. Preferred carriers areedible oils, for example, corn or canola oils. Polyethylene glycols,e.g. PEG, are also preferred carriers.

The formulations for oral administration may comprise a non-toxic,pharmaceutically acceptable, inert carrier such as lactose, starch,sucrose, glucose, methyl cellulose, magnesium stearate, dicalciumphosphate, calcium sulfate, mannitol, sorbitol, cyclodextrin,cyclodextrin derivatives, or the like.

Capsule or tablets can be easily formulated and can be made easy toswallow or chew. Tablets may contain suitable carriers, binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, flow-inducing agents, or melting agents. A tablet may be made bycompression or molding, optionally with one or more additionalingredients. Compressed tables may be prepared by compressing the activeingredient in a free flowing form (e.g., powder, granules) optionallymixed with a binder (e.g., gelatin, hydroxypropylmethylcellulose),lubricant, inert diluent, preservative, disintegrant (e.g., sodiumstarch glycolate, cross-linked carboxymethyl cellulose) surface-activeor dispersing agent. Suitable binders include starch, gelatin, naturalsugars such as glucose or beta-lactose, corn sweeteners, natural andsynthetic gums such as acacia, tragacanth, or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, or the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, or the like. Disintegrators include, for example, starch,methyl cellulose, agar, bentonite, xanthan gum, or the like. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered active ingredient moistened with an inert liquid diluent.

The tablets may optionally be coated or scored and may be formulated soas to provide slow- or controlled-release of the active ingredient.Tablets may also optionally be provided with an enteric coating toprovide release in parts of the gut other than the stomach.

Exemplary pharmaceutically acceptable carriers and excipients that maybe used to formulate oral dosage forms of the present invention aredescribed in U.S. Pat. No. 3,903,297 to Robert, issued Sep. 2, 1975,incorporated by reference herein. Techniques and compositions for makingdosage forms useful in the present invention are described in thefollowing references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker& Rhodes, Editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms:Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms2nd Edition (1976).

Formulations suitable for topical administration in the mouth whereinthe active ingredient is dissolved or suspended in a suitable carrierinclude lozenges which may comprise the active ingredient in a flavoredcarrier, usually sucrose and acacia or tragacanth; gelatin, glycerin, orsucrose and acacia; and mouthwashes comprising the active ingredient ina suitable liquid carrier.

Topical applications for administration according to the method of thepresent invention include ointments, cream, suspensions, lotions,powder, solutions, pastes, gels, spray, aerosol or oil. Alternately, aformulation may comprise a transdermal patch or dressing such as abandage impregnated with an active ingredient and optionally one or morecarriers or diluents. To be administered in the form of a transdermaldelivery system, the dosage administration will, of course, becontinuous rather than intermittent throughout the dosage regimen.

The topical formulations may desirably include a compound that enhancesabsorption or penetration of the active ingredient through the skin orother affected areas. Examples of such dermal penetration enhancersinclude dimethylsulfoxide and related analogues.

The oil phase of an emulsion used to treat subjects in the presentinvention may be constituted from ingredients known to one of skill inthe art in light of the present disclosure. An emulsion may comprise oneor more emulsifiers. For example, an oily phase may comprise at leastone emulsifier with a fat or an oil, with both a fat and an oil, or ahydrophilic emulsifier may be included together with a lipophilicemulsifier that acts as a stabilizer. Together, the emulsifier(s), withor without stabilizer(s), make up an emulsifying wax, and the waxtogether with the oil and/or fat make up the emulsifying ointment basethat forms the oily dispersed phase of the cream formulations.

Emulsifiers and emulsion stabilizers suitable for use in the formulationinclude Tween 60, Span 80, cetosteryl alcohol, myristyl alcohol,glyceryl monostearate and sodium lauryl sulphate, paraffin, straight orbranched chain, mono-or dibasic alkyl esters, mineral oil. The choice ofsuitable oils or fats for the formulation is based on achieving thedesired cosmetic properties, the properties required and compatibilitywith the active ingredient.

Compounds of the present invention may also be administered vaginally,for example, as pessaries, tampons, creams, gels, pastes, foams or sprayformulations containing appropriate carriers in addition to the activeingredient. Such carriers are known in the art in light of the presentdisclosure.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising, for example, cocoa butter or asalicylate.

Formulations suitable for nasal administration may be administered in aliquid form, for example, nasal spray, nasal drops, or by aerosoladministration by nebulizer, including aqueous or oily solutions of theactive ingredient. Formulations for nasal administration, wherein thecarrier is a solid, include a coarse powder having a particle size, forexample, of less than about 100 microns, preferably less than about 50microns, which is administered in the manner in which snuff is taken,i.e., by rapid inhalation through the nasal passage from a container ofthe powder held close up to the nose.

Formulations suitable for parenteral administration include aqueous andnon-aqueous formulations isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending systems designed to target the compound to bloodcomponents or one or more organs. The formulations may be presented inunit-dose or multi-dose sealed containers, for example, ampoules orvials. Extemporaneous injections solutions and suspensions may beprepared from sterile powders, granules and tablets of the kindpreviously described. Parenteral and intravenous forms may also includeminerals and other materials to make them compatible with the type ofinjection or delivery system chosen.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),or related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents and,if necessary, buffer substances. Antioxidizing agents, such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid saltsthereof, or sodium EDTA. In addition, parenteral solutions may containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,or chlorobutanol. Suitable pharmaceutical carriers are described inRemington, cited supra.

The present invention additionally contemplates administering compoundsof the herein described invention for use in the form of veterinaryformulations, which may be prepared, for example, by methods that areconventional in the art in light of the present disclosure.

Useful pharmaceutical dosage formulations for administration of thecompounds of the present invention are illustrated as follows:

Capsules: A large number of unit capsules are prepared by fillingstandard two-piece hard gelatin capsules each with 100 milligrams ofpowdered active ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules: A mixture of active ingredient in a digestibleoil such as soybean oil, cottonseed oil or olive oil is prepared andinjected by means of a positive displacement pump into gelatin to formsoft gelatin capsules containing 100 milligrams of the activeingredient. The capsules are washed and dried.

Tablets: A large number of tablets are prepared by conventionalprocedures so that the dosage unit was 100 milligrams of activeingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams ofmagnesium stearate, 275 milligrams of microcrystalline cellulose, 11milligrams of starch and 98.8 milligrams of lactose. Appropriatecoatings can be applied to increase palatability or delay absorption.

Injectable: A parenteral composition suitable for administration byinjection is prepared by stirring 1.5% by weight of active ingredient in10% by volume propylene glycol and water. The solution is made isotonicwith sodium chloride and sterilized.

Suspension: An aqueous suspension is prepared for oral administration sothat each 5 ml contains 100 mg of finely divided active ingredient, 200mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 ml of vanillin.

Compounds of the present invention may be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may be coupled with soluble polymersas targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxylpropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention can be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

H. Method of Treatment

The method of treatment can be any suitable method which is effective inthe treatment of the particular cancer or viral infection that is beingtreated. Treatment includes administering a therapeutically effectiveamount of the compounds of the present invention in a form describedhereinabove, to a subject in need of treatment.

Compounds of the present invention can be administered by any means thatproduces contact of the active agent with the agent's site of action inthe body, for example, suitable means including, but not limited to,oral, rectal, nasal, topical (including transdermal, aerosol, buccal orsublingual), vaginal, parenteral (including subcutaneous, intramuscular,intravenous or intradermal), intravesical, or injection into or aroundthe cancer or site of viral infection. They can be administered by anyconventional means available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or in acombination of therapeutics. Preferably, compounds of the presentinvention are administered as a pharmaceutical formulation comprising atleast one compound of the present invention, as defined above, togetherwith one or more pharmaceutically acceptable carriers. It can beco-administered in the form of a tablet or capsule, as an agglomeratedpowder, or in a liquid form, or as a liposome.

The preferred route will vary with the condition and age of therecipient, virus or cancer being treated nature of the disorder, orseverity of disorder. It is believed that oral administration, orparenteral treatment is the preferred method of administering thecompounds to subjects in need thereof.

In each of the above-described methods, the administering may be invivo, or may be ex vivo. In vivo treatment is useful for treatingdiseases in a mammal, preferably the mammal is a human; and ex vivotreatment is useful for purging body fluids, such as blood, plasma, bonemarrow, and the like, for return to the body. The nation's blood supplyis currently tested for antibodies to HIV. However, the test is stillimperfect and samples that yield negative tests can still contain HIVvirus. Treating blood and blood products with the compounds of thepresent invention can add an extra margin of safety to kill anyretrovirus that may have gone undetected. Body tissue may be internal orexternal to an animal body, or, for example, may be the surface skin ofthe animal.

I. Combination Therapy

Compounds of the present invention may additionally be combined withchemotherapeutic agents and/or potentiators to provide a combinationtherapy. Combination therapy is intended to include any chemicallycompatible combination of a compound of the present invention with othercompounds of the present invention or other compounds outside of thepresent invention, as long as the combination does not eliminate theactivity of the compound of the present invention. For example, one ormore compounds may be combined with a potentiator or with achemotherapeutic agent. In the case of retroviral infection, acombination therapy with nucleoside analogues such as AZT, nonnucleosidereverse transcriptase inhibitors, TC-3, or protease inhibitors iscontemplated by the present invention. In the case of hepatitis,acyclovir, famciclovir or valacyclovir, Ribavirin, interferon, orcombinations of Ribavirin and interferon or beta globulin iscontemplated as a combination therapy. For herpes, a recombinant alphainterferon can be used as a combination therapy. The active agent can becoadministered, for example, in the form of a tablet or capsule,liposome, as an agglomerated powder, or in a liquid form. The amount ofchemotherapeutic agent or potentiator used can be lower than that of thebenzimidazole derivative. It will be present in a dosage unit in anamount that provides an operative combination with the benzimidazolederivative. The dosage of the chemotherapeutic agent or the potentiatorcan range from about 0.5 mg/kg body weight to about 400 mg/kg bodyweight.

Combination therapy can be sequential, that is the treatment with oneagent first and then the second agent, or it can be treatment with bothagents at the same time. The sequential therapy can be within areasonable time after the completion of the first therapy beforebeginning the second therapy. The treatment with both agents at the sametime can be in the same daily dose or in separate doses. For example,treatment with one agent on day 1 and the other on day 2. The exactregimen will depend on the disorder being treated, the severity of thedisorder, and the response to the treatment.

In addition to the use of chemotherapeutic agents and potentiators, abenzimidazole derivate or a salt or a prodrug thereof can be combinedwith a fungicide or an herbicide. Preferred herbicides and fungicidesinclude carbendazim, fluoconazole, benomyl, glyphosate, andpropicodazole.

J. Pharmaceutical Kits

The present invention also includes pharmaceutical kits useful, forexample, for the treatment of cancer or viral infection. The kitscomprise one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of thepresent invention. Such kits can further include, if desired, one ormore of various conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instruction, such as printed instructions forexample, either as inserts or as labels, the instruction indicatingquantities of the components to be administered, guidelines foradministration, and/or guidelines for mixing the components, can also beincluded in the kit.

K. Studies

The following studies were performed to test the effectiveness of thebenzimidazole derivatives of the present invention against certaincancers and viral infections.

Colon and Melanoma Tumor Cells Test

The following cell culture tests were performed to test the toxicity ofbenzimidazole derivative compounds of the present invention on colon andmelanoma tumor cells. The viability of the cells were tested by lookingat MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide)reduction. MTT assay is a well known measure of cell viability.

The colon tumor cells (HT29) and the melanoma cells (B16 murinemelanoma) were seeded (1000-2000 cells) into each well of a 96-wellmicrotiter plate and allowed to grow. Twenty-four hours later,increasing concentrations of each benzimidazole derivative were added tothe plates and the cells were allowed to incubate for 3-6 days in thepresence of the drugs. MTT reagent was then added to the wells andallowed to incubate for 4 hours at 37° C., after which the formazanmetabolite was solubilized with acidic isopropanol and the absorbancewas read. Experimental controls included blank wells to which no cellswere added (zero point of formazan absorbance) and control wells towhich no drug was added (highest level of formazan absorbance). Eachdrug concentration was tested in duplicate and the resulting averageabsorbance was plotted against drug concentration using the EZ-ED50computer program on a personal computer interfaced to the microtiterplate reader. The program fit the resulting curves to a four-parameterequation:$Y = {\frac{A_{m\quad a\quad x} - A_{m\quad i\quad n}}{\left( {1 + \frac{X}{IC50}} \right)^{n}} + A_{m\quad i\quad n}}$

where A_(max) and A_(min) are, respectively, the absorbances in theabsence and presence of highest drug concentration, X is the drugconcentration and Y is the absorbance at that concentration, n is theslope of the curve, and IC₅₀ is the concentration of drug that gives 50%growth inhibition. The IC₅₀ value is then derived from this equation byEZ-ED50. The IC₅₀ values for growth inhibition of both B16 and HT29cancer cell lines are reported in Table 4 below (Y═H unless otherwiseindicated).

TABLE 4 MTT Assay - Growth Inhibitory Activity IC₅₀ (μM) Cpd. No. MurineMelanoma Human Colon Carcinoma 1-1 14.8 23.6 1-2 29.5 38.4 1-3 8.9 27.11-4 73.5 66.0 1-5 32.5 52.0 1-6 33.9 31.9 1-7 115.6 80.6 2-1 181.9 252.82-2 1.7 2.0 2-3 14.2 11.1 2-4 200.6 212.6 2-5 25.6 31.3 2-6 292.6 374.72-7 159.5 119.2 2-8 1.8 1.9 2-9 >100 >100 2-10 771.5 83.8 2-10* 112.891.5 2-11 13.7 45.5 2-12 3.1 4.1 2-12* 0.98 1.9 2-13* 0.63 0.29 *Y = Cl,at the 5(6) position

Microtubule Inhibition Assay

The benzimidazole derivatives of this invention were evaluated for theirability to inhibit formation of microtubules, following the procedure ofLuduena, R. F. and M. C. Roach (Pharmacol. Ther. 49: 133-152 (1991)).Tubulin was purified from bovine brain by a cycle of assembly anddisassembly, followed by phosphocellulose chromatography and gelfiltration (Fellous, A. et al., Eur. J. Biochem. 78(1): 167-174 (1977)).The assay was performed by preparing a sample of tubulin protein underconditions which promote polymerization into microtubules (Prasad, V. etal., J. Protein Chem. 11(5): 509-515 (1992)), then adding thebenzimidazole derivatives, at 2 μM, and following the time course ofpolymerization. Microtubule polymerization was followed by performingthe reaction in a cuvette and monitoring UV absorbance at 350 nm,allowing direct visualization of the time course of the polymerization.After 30 minutes, polymerization was complete and the percent inhibitionof polymerization was calculated as the final absorbance of the reactiontaken as a percentage of the final absorbance of a controlpolymerization reaction run in parallel without drug added. These dataare reported in Table 5 below.

TABLE 5 Tubulin Polymerization Inhibition Cpd. No. % Inhibition 1-1 251-2 28 1-3 20 1-4 63 1-5 38 1-6 31 1-7 15 2-1 17 2-2 3 2-3 19 2-4 10 2-531 2-6 0 2-7 21 2-8 15 2-9 18 2-10 36 2-10* 23 2-11 48 2-12 0 2-12* 222-13* 50 *Y = Cl, at the 5(6) position

DNA Binding Assay

The DNA binding assay was performed in a manner very similar to that ofthe MTT cell growth inhibition assay above. The assay was based upon theability of the test compounds to displace methyl green (Sigma) from DNAand the resultant hydration of the free methyl green molecule to acolorless derivative (Burres, N. S. et al., J. Nat. Prod. 55(11):1582-1587 (1992); Kim and Nordén, FEBS Lett. 315(1): 61-64 (1993)). Asfor the MTT assay, each drug concentration was assayed in duplicate andthe data were averaged before analysis. Experimental controls in thisassay included wells containing free methyl green solution with no DNA,for fully decolorized background absorbance, and methyl green-DNAcomplex (Sigma) without drug, for the highest possible methyl greenabsorbance. Methyl green-DNA in buffer was added to each well to obtainA₆₅₅ of approximately 0.7. Serial dilutions of drug in buffer were addedand the plates were mixed, then allowed to stand at room temperature for24 hours to allow for displacement and hydration of the free methylgreen. The absorbance at 655 nm was measured as a function of added drugconcentration in an automated microplate reader, and the data werereduced by the computer program EZ-ED50 to derive IC₅₀ values(concentration at which 50% of the methyl green is displaced from DNA).

None of the benzimidazole derivatives listed in Table 4 or 5 showed anyDNA interaction by this assay.

EXAMPLES Example 1

Synthesis of Cpd. No. 1-4

0.200 Gram (1.5 mmol) of 2-aminobenzimidazole was dissolved in 4 mL drypyridine and one equivalent (1.5 mmol, 200 mg) of benzyl isocyanate wasadded under argon. The mixture was stirred for 16 hours under argon at23° C. and another equivalent of benzyl isocyanate was then added. Afterfour more hours stirring under argon at 23° C., the mixture was pouredinto 20 mL water to precipitate the product. The product was collectedby filtration, washed with water and dried under reduced pressure for 16hours to provide 0.234 g (0.879 mmol, 58.6% yield) of white powder.

Example 2

Synthesis of Cpd. No. 1-5

0.200 Gram (1.5 mmol) of 2-aminobenzimidazole was dissolved in 4 mL drypyridine and one equivalent (1.5 mmol, 256 mg) of benzyl chloroformatewas added under argon. The mixture was stirred for 16 hours under argonat 23° C. and another equivalent of benzyl chloroformate was then added.After four more hours stirring under argon at 23° C., the mixture waspoured into 20 mL water to precipitate the product. The product wascollected by filtration, washed with water and dried under reducedpressure for 16 hours to provide 0.168 g (0.629 mol, 41.9% yield) ofwhite powder.

Example 3

Synthesis of Cpd. No. 2-11

0.112 Gram (0.421 mmol) of Cpd. No. 1-4, from Example 1, was dissolvedin 1 mL dry pyridine and heated to 80° C. for 5 hours with stirring. SixmL water was added to the mixture with stirring and the solidprecipitate was collected by filtration, washed with water, and driedunder reduced pressure for 16 hours. 0.074 g (0.277 mmol, 65.8% yield)of off-white powdery product was obtained.

Example 4

Synthesis of Cpd. No. 2-9

0.040 Gram (0.150 mmol) of Cpd. No. 1-5, from Example 2, was dissolvedin 4 mL toluene and heated to 110° C. with stirring for 24 hours. Themixture was cooled in an ice-water bath and the precipitated solidcollected by filtration to provide 0.024 g (0.090 mmol, 60% yield) ofproduct as a white powder.

Example 5

Synthesis of Cpd. No. 2-7

0.025 Gram (0.131 mmol) of methyl 2-aminobenzimidazole carbamate wasmixed with 2 mL of toluene and 0.696 g (6.55 mmol) of diethylene glycol.Three mg of aluminum isopropoxide was added and the mixture was heatedto 110° C. for 15 hours. The toluene was evaporated under a stream ofargon with continued heating, then the heat was removed and the residuewas treated with 4 mL of boiling water. The resulting mixture was cooledto 23° C., then stored 18 hours at 4° C. The precipitate that formed wascollected by filtration and dried under reduced pressure to provide0.029 g (0.109 mmol, 83.2% yield) of product as off-white flakes.

Example 6

Synthesis of Cpd. No. 2-5

0.025 Gram (0.131 mmol) of methyl 2-aminobenzimidazole carbamate wasmixed with 2 mL of toluene and 0.817 g (6.55 mmol) of2-(2-chloroethoxy)ethanol. Three mg of aluminum isopropoxide was addedand the mixture was heated to 110° C. for 15 hours. The toluene wasevaporated under a stream of argon with continued heating, then the heatwas removed and the residue was treated with 4 ml of boiling water. Theresulting mixture was cooled to 23° C., then stored 18 hours at 4° C.The precipitate that formed was collected by filtration and dried underreduced pressure to provide 0.026 g (0.09 mmol, 68.7% yield) of productas off-white powder.

Example 7

Synthesis of Cpd. No. 2-4

0.025 g (0.131 mmol) of methyl 2-aminobenzimidazole carbamate was mixedwith 2 ml of toluene and 0.689 g (6.55 mmol) of2-(2-aminoethoxy)ethanol. Three mg of aluminum isopropoxide was addedand the mixture was heated to 110° C. for 15 hours. The toluene wasevaporated under a stream of argon with continued heating, then the heatwas removed and the residue was treated with 4 ml of boiling water. Theresulting mixture was cooled to 23° C., then stored 18 hours at 4° C.The precipitate that formed was collected by filtration and dried underreduced pressure to provide 0.009 g (0.034 mmol, 25.9% yield) of productas colorless platelike crystals.

What is claimed is:
 1. A compound having the following formula A-4:

wherein, R₃ is haloalkenyl, hydroxyalkyl, alkoxyalkyl,poly(alkoxy)alkyl, hydroxyalkoxyalkyl, hydroxypoly(alkoxy)alkyl,haloalkoxyalkyl, halopoly(alkoxy)alkyl, or aminoalkyl; each of X and Yis independently hydrogen, alkyl, alkenyl, cycloalkyl, haloalkyl,haloalkenyl, halogen, nitro, or amino; and n is 1, 2, or
 3. 2. Acompound according to claim 1, wherein X is hydrogen, and Y is hydrogenor chloro and is in the 5(6) position.
 3. The compound of claim 1wherein R₃ is aminoalkyl.
 4. The compound of claim 1 wherein R₃ ishydroxyalkoxyalkyl.
 5. A pharmaceutical composition comprising atherapeutically effective amount of a compound of the following formulaA-4:

wherein R₃ is haloalkyl, haloalkenyl, substituted or unsubstitutedbenzyl, hydroxyalkyl, alkoxyalkyl, poly(alkoxy)alkyl,hydroxyalkoxyalkyl, hydroxypoly(alkoxy)alkyl, haloalkoxyalkyl,halopoly(alkoxy)alkyl, or aminoalkyl; and Y is independently hydrogen,alkyl, alkenyl, cycloalkyl, haloalkyl, haloalkenyl, halogen, nitro, oramino; and, a pharmaceutically acceptable carrier.
 6. The composition ofclaim 5 wherein R₃ is haloalkyl.
 7. The composition of claim 6 wherein Yis halogen and the halogen is chloro.
 8. The composition of claim 5wherein R₃ is substituted benzyl.
 9. The composition of claim 5 whereinR₃ is unsubstituted benzyl.
 10. A pharmaceutical composition accordingto claim 5 wherein Y is hydrogen or halogen and the halogen is chloro.11. A pharmaceutical composition according to claim 5 wherein saidcompound is micronized and said composition is suitable foradministration by injection.
 12. A unit dosage form comprising acompound of the following formula A-4:

wherein, R₃ is haloalkyl, haloalkenyl, substituted or unsubstitutedbenzyl, hydroxyalkyl, alkoxyalkyl, poly(alkoxy)alkyl,hydroxyalkoxyalkyl, hydroxypoly(alkoxy)alkyl, haloalkoxyalkyl,halopoly(alkoxy)alkyl, or aminoalkyl; each of X and Y is independentlyhydrogen, alkyl, alkenyl, cycloalkyl, haloalkyl, haloalkenyl, halogen,nitro, or amino; and n is 1, 2, or 3; and, a pharmaceutically acceptablecarrier.
 13. A unit dosage form according to claim 12 which comprisesfrom 1 mg to 1000 mg of said compound.
 14. A unit dosage form accordingto claim 12 wherein said compound is micronized and said carrier issuitable for administration by injection.
 15. A pharmaceutical kitcomprising: a therapeutically effective amount of a compound of thefollowing formula A-4:

 wherein, R₃ is haloalkyl, haloalkenyl, substituted or unsubstitutedbenzyl, hydroxyalkyl, alkoxyalkyl, poly(alkoxy)alkyl,hydroxyalkoxyalkyl, hydroxypoly(alkoxy)alkyl, haloalkoxyalkyl,halopoly(alkoxy)alkyl, or aminoalkyl; each of X and Y is independentlyhydrogen, alkyl, alkenyl, cycloalkyl, haloalkyl, haloalkenyl, halogen,nitro, or amino; and n is 1,2,or 3; and, instruction for use in treatingcancer or a viral infection.
 16. A pharmaceutically acceptable salt of acompound of the following formula A-4:

wherein, R₃ is haloalkyl, haloalkenyl, substituted or unsubstitutedbenzyl, hydroxyalkyl, alkoxyalkyl, poly(alkoxy)alkyl,hydroxyalkoxyalkyl, hydroxypoly(alkoxy)alkyl, haloalkoxyalkyl,halopoly(alkoxy)alkyl, or aminoalkyl; each of X and Y is independentlyhydrogen, alkyl, alkenyl, cycloalkyl, haloalkyl, haloalkenyl, halogen,nitro, or amino; and n is 1,2, or
 3. 17. A pharmaceutically acceptablesalt according to claim 16 which is hydrochloride salt.
 18. A prodrug ofa compound of the following formula A-4:

wherein, R₃ is haloalkyl, alkenyl, haloalkenyl, cycloalkyl,cycloalkalkyl, heterocycloalkyl, heterocycloalkalkyl, substituted orunsubstituted benzyl, hydroxyalkyl, alkoxyalkyl, poly(alkoxy)alkyl,hydroxyalkoxyalkyl, hydroxypoly(alkoxy)alkyl, haloalkoxyalkyl,halopoly(alkoxy)alkyl, or aminoalkyl; each of X and Y is independentlyhydrogen, alkyl, alkenyl, cycloalkyl, haloalkyl, haloalkenyl, halogen,nitro, or amino; and n is 1, 2, or
 3. 19. A pharmaceutical compositioncomprising a therapeutically effective amount of a pharmaceuticallyacceptable salt of a compound of the following formula A-4:

wherein, R₃ is haloalkyl, haloalkenyl, substituted or unsubstitutedbenzyl, hydroxyalkyl, alkoxyalkyl, poly(alkoxy)alkyl,hydroxyalkoxyalkyl, hydroxypoly(alkoxy)alkyl, haloalkoxyalkyl,halopoly(alkoxy)alkyl, or aminoalkyl; each of X and Y is independentlyhydrogen, alkyl, alkenyl, cycloalkyl, haloalkyl, haloalkenyl, halogen,nitro, or amino; and n is 1,2,or3; and, a pharmaceutically acceptablecarrier.
 20. A pharmaceutical composition according to claim 19 whereinsaid pharmaceutically acceptable salt is selected from the groupconsisting of chloride, bromide, sulfate, nitrate, phosphate, sulfonate,formate, tartrate, maleate, malate, citrate, benzoate, salicylate,ascorbate, and mixtures thereof.
 21. A pharmaceutical compositionaccording to claim 19 wherein said pharmaceutically acceptable salt ishydrochloride salt.
 22. A pharmaceutically acceptable salt according toclaim 16 which is selected from the group consisting of chloride,bromide, sulfate, nitrate, phosphate, sulfonate, formate, tartrate,maleate, malate, citrate, benzoate, salicylate, ascorbate, and mixturesthereof.
 23. A pharmaceutical composition comprising a therapeuticallyeffective amount of a prodrug of a compound of the following formulaA-4:

wherein, R₃ is haloalkyl, alkenyl, haloalkenyl, cycloalkyl,cycloalkalkyl, heterocycloalkyl, heterocycloalkalkyl, substituted orunsubstituted benzyl, hydroxyalkyl, alkoxyalkyl, poly(alkoxy)alkyl,hydroxyalkoxyalkyl, hydroxypoly(alkoxy)alkyl, haloalkoxyalkyl,halopoly(alkoxy)alkyl, or aminoalkyl; each of X and Y is independentlyhydrogen, alkyl, alkenyl, cycloalkyl, haloalkyl, haloalkenyl, halogen,nitro, or amino; and n is 1,2, or 3; and, a pharmaceutically acceptablecarrier.
 24. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the following formula A-4:

wherein, R₃ is haloalkyl, alkenyl, haloalkenyl, cycloalkyl,cycloalkalkyl, heterocycloalkyl, heterocycloalkalkyl, substituted orunsubstituted benzyl, hydroxyalkyl, alkoxyalkyl, poly(alkoxy)alkyl,hydroxyalkoxyalkyl, hydroxypoly(alkoxy)alkyl, haloalkoxyalkyl,halopoly(alkoxy)alkyl, or aminoalkyl; each of X and Y is independentlyhydrogen, alkyl, alkenyl, cycloalkyl, haloalkyl, haloalkenyl, halogen,nitro, or amino; and n is 1, 2, or 3; and, a pharmaceutically acceptablecarrier selected from the group consisting of a liposome deliverysystem, a soluble polymer to which said compound is coupled, and abiodegradable polymer to which said compound is coupled.
 25. A unitdosage form comprising a compound of the following formula A-4:

wherein, R₃ is haloalkyl, alkenyl, haloalkenyl, cycloalkyl,cycloalkalkyl, heterocycloalkyl, heterocycloalkalkyl, substituted orunsubstituted benzyl, hydroxyalkyl, alkoxyalkyl, poly(alkoxy)alkyl,hydroxyalkoxyalkyl, hydroxypoly(alkoxy)alkyl, haloalkoxyalkyl,halopoly(alkoxy)alkyl, or aminoalkyl; each of X and Y is independentlyhydrogen, alkyl, alkenyl, cycloalkyl, haloalkyl, haloalkenyl, halogen,nitro, or amino; and n is 1, 2, or 3; and, a pharmaceutically acceptablecarrier selected from the group consisting of a liposome deliverysystem, a soluble polymer to which said compound is coupled, and abiodegradable polymer to which said compound is coupled.